Although it is widely accepted that the accumulation of monomeric amyloid-beta protein into insoluble deposits is the primary event driving pathogenesis of Alzheimer's disease, the underlying mechanism by which amyloid-beta aggregates result in neurotoxicity is still unclear. The central hypothesis of this research proposal is that the adsorption, incorporation, and disruption of lipid membranes by amyloid-beta is the primary mechanism by which the protein exerts neurotoxicity. To test this hypothesis, a comprehensive biophysical study will be carried out to characterize amyloid-beta-membrane interactions and to elucidate their roles in neurotoxicity. In particular, the effects of different amyloid-beta association states and the presence of cholesterol and metal ions (factors that impact amyloid-beta neurotoxicity in vitro and in vivo) on amyloid-beta-membrane interactions, amyloid-beta fibrillogenesis, and amyloid-beta-induced neurotoxicity will be investigated in detail. The link between amyloid-beta-membrane interactions and neurotoxicity will be evaluated